H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor β gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22)
H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor β gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22)
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DOI：
10.1182/blood.v97.12.3910
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发表时间：
2001-06-15
期刊：
影响因子：
20.3
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
--
作者：
Schwaller, J;Anastasiadou, E;Gilliland, DG
报道了与非典型慢性粒细胞白血病（CML）相关的t（5;10）（q33; q22）基因的分子克隆。荧光原位杂交（FISH）、Southern印迹和逆转录酶-聚合酶链反应分析表明，易位导致H4/血小板衍生生长因子受体β R（PDGF β R）融合转录本，该转录本将来自H4的5 '序列与编码跨膜、WW样和酪氨酸激酶结构域的3 ' PDGF β R序列框内融合。FISH结合免疫表型分析显示t（5;10）（q33;q22）在CD 13（+）和CD 14（+）细胞中存在，而在CD 3（+）和CD 19（+）细胞中未观察到。H4先前已经作为RET的融合伴侣与乳头状甲状腺癌的发病机制有关。H4/RET融合体掺入了H4的101个氨基酸，预测编码亮氨酸拉链二聚化结构域，而H4/PDGF β R融合体掺入了H4的另外267个氨基酸，H4/PDGF β R的逆转录病毒转导，但不是激酶失活突变体，赋予Ba/F3细胞因子非依赖性生长，并在鼠骨髓移植转化试验中引起T细胞淋巴母细胞性淋巴瘤。突变分析显示，氨基末端H4亮氨酸拉链结构域（氨基酸55-93）以及H4氨基酸101至386是有效诱导Ba/F3细胞的因子非依赖性生长所需的。在PDGF β R WW样结构域566/593位的色氨酸-丙氨酸取代，或PDGF β R 579/581位的酪氨酸-苯丙氨酸取代损害了Ba/F3细胞的因子非依赖性生长。H4/PDGF β R是一种在t（5;10）（q33;q22）非典型CML中表达的癌蛋白，并且需要H4部分中的二聚基序以及与PDGFPR的信号转导有关的残基，以有效诱导Ba/F3细胞的因子非依赖性生长，（C）2001，美国血液学学会。
The molecular cloning of the t(5;10)(q33; q22) associated with atypical chronic myeloid leukemia (CML) is reported. Fluorescence in situ hybridization (FISH), Southern blot, and reverse transcriptase-polymerase chain reaction analysis demonstrated that the translocation resulted in an H4/platelet-derived growth factor receptor betaR (PDGF betaR) fusion transcript that incorporated 5 ' sequences from H4 fused in frame to 3 ' PDGF betaR sequences encoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combined with immunophenotype analysis showed that t(5;10)(q33;q22) was present in CD13(+) and CD14(+) cells but was not observed in CD3(+) or CD19(+) cells. H4 has previously been implicated in pathogenesis of papillary thyroid carcinoma as a fusion partner of RET, The H4/RET fusion incorporates 101 amino acids of H4, predicted to encode a leucine zipper dimerization domain, whereas the H4/PDGF betaR fusion incorporated an additional 267 amino acids of H4, Retroviral transduction of H4/PDGF betaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells. Tryptophan-to-alanine substitutions in the PDGF betaR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGF betaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGF betaR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues implicated in signal transduction by PDGFPR, for efficient induction of factor-independent growth of Ba/F3 cells, (C) 2001 by The American Society of Hematology.